Staphylococcus aureus (S. aureus) is an opportunistic bacterial pathogen that may cause a variety of diseases in humans ranging from moderate to severe skin and soft tissue infections to very serious diseases such as septic shock, toxic shock syndrome or pneumonia. Some of these infections may be fatal, in particular hospital-associated infections, which are often complicated by the fact that many hospital strains are resistant to antibiotics such as methicillin. Different strategies to prevent and/or treat S. aureus infections by passive immunization through the use of therapeutic antibodies or active immunization by vaccination are currently under development. Virulence factors of S. aureus are potent vaccine targets. However, it is likely that monovalent vaccine targeting only one virulence factor will not be enough to prevent S. aureus infections because the bacteria have developed different strategies to evade the host immune system. Antigenic variability among S. aureus strains or even during the life of the bacteria is another strategy. For instance, the capsular polysaccharide of S. aureus which is a well-known virulence factor is subject to variations among strains. Type 5 S. aureus strains express a type 5 capsular polysaccharide made of repeating units having the following structure: →4)-β-D-ManNAcA-(1→4)-α-L-FucNAc(3OAc)(1→3)-β-D-FucNAc-(1→while Type 8 S. aureus strains express a type 8 capsular polysaccharide made of repeating units having the following structure: →3)-β-D-ManNAcA(4OAc)-(1→3)-α-L-FucNAc(1→3)-α-D-FucNAc-(1→. Type 5 and type 8 strains account for approximately 88% of all clinical isolates. The remaining isolates that do not express type 5 or type 8 capsular polysaccharide have been described as carrying an antigen called the 336 antigen. The 336 antigen as described in WO 2007/053176 is a teichoic acid like structure comprising repeating units of 1,5 ribitol phosphate in which the 3-position of the ribitol is substituted by N-acetyl-β-D-glucosaminyl residues. Following the failure of a bivalent vaccine (staphVAX) comprising type 5 and type 8 capsular polysaccharides conjugated to a carrier protein in a phase III clinical trial, a second generation staphVAX vaccine is being developed, which comprises the 336 antigen in addition to the S. aureus type 5 and type 8 antigens and which is intended to provide a better coverage of clinical isolates than the previous version. This evolution of the staphVAX vaccine reflects the current strategy for S. aureus vaccine development which is to include more and more antigens in the vaccine composition in order to overcome the immune evasion mechanisms and the antigenic variability among S. aureus strains. Nevertheless there is a need to rationalize as much as possible the number of antigens to be included in the vaccine composition to limit the costs associated with the development and production of a multivalent vaccine. The identification of antigens that induce cross reactive antibodies recognizing both homologous and heterologous antigenic structures that are broadly expressed among S. aureus strains could be an efficient way to reduce the number of antigens to be combined in a vaccine against S. aureus. In this regard, WO 2007/057176 describes a conjugate form of the 336 antigen that elicits cross reactive antibodies that bind to both the homologous 336 antigen and the heterologous PS1 polysaccharide from Staphylococcus epidermidis (S. epidermidis). While this conjugate elicits inter species cross reactive antibodies (since the antibodies recognizes a heterologous antigenic structure expressed by S. epidermidis), there is no clear evidence that the antibodies recognize heterologous antigenic structures expressed by S. aureus strains.
EP 2848257 proposes a vaccine composition for preventing Staphylococcus aureus infection comprising a native form of WTA containing a ribitol-phosphate which has been modified by N-acetylglucosamine (GlcNAc), which comprises, as an active ingredient:
(i) a ribitol-phosphate which has been modified only by GlcNAc in a β-configuration and not by GlcNAc in an α-configuration;
(ii) a repeating unit of the ribitol-phosphate which has been modified only by GlcNAc in a β-configuration and not by GlcNAc in an α-configuration; or
(iii) wall teichoic acid (WTA) containing the repeating unit of the ribitol-phosphate which has been modified only by GlcNAc in a β-configuration and not by GlcNAc in an α-configuration.
In the representation provided in FIG. 3 of this patent application, the GlcNAc is at position 2 of the ribitol-phosphate units. In order to improve its antigenicity, a carrier or an adjuvant can be added.
WO 2006/065,553 discloses glycoconjugate vaccines comprising a therapeutically effective amount of a capsular polysaccharide of S. aureus conjugated to a carrier protein, where the polysaccharide comprises an amount of peptidoglycan (e.g. at least about 5% (w/w)), which is effective to enhance properties of the vaccine, for example by improved conjugation efficiency of the polysaccharide to the carrier protein or by enhanced immunogenicity of the vaccine.
The inventors have now identified new antigenic structures that elicit cross reactive antibodies recognizing heterologous antigenic structures expressed by S. aureus strains so that the antibodies induced by such antigenic structures recognize a broad panel of S. aureus strains. Accordingly these new antigenic structures represent useful candidate vaccines since they contribute to the reduction of the number of antigens to be incorporated in an S. aureus vaccine.